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A kind of synthetic method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate

A technology of benzofuran and ethyl carboxylate, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high production cost, low product purity, low yield and the like, achieves simple reaction control conditions and post-processing process, and is concise. Operation, Effects of Raw Materials in Broad Synthetic Routes

Active Publication Date: 2016-04-06
BEIJING BEILU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the synthetic method of above-mentioned prior art, not only have used the bigger toluene solvent system of toxicity, and temperature is difficult for controlling in the reaction process, and temperature is too low to react incompletely, and the color of solution of too high temperature turns black, and by-product increases, and product purity Not high, and the heating time is too long and the yield is not high, resulting in high production cost of the product, making it difficult for large-scale industrial production

Method used

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  • A kind of synthetic method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate
  • A kind of synthetic method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate
  • A kind of synthetic method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1: Preparation of 3-[2-hydroxyl-5-(piperazin-1-yl)]phenyl-2-propenal (1)

[0034] N 2 Under air protection, add 40g (0.6mol) zinc and 2LTHF to a dry four-neck flask with magnetic stirring, start stirring, cool the reaction system to -20~-15°C, and drop 32.5mL (0.3mol) TiCl 4 , Control the temperature of the system at -20~-15°C during the dropping process. After the dropwise addition, the temperature was raised to reflux for 3h, and again under N 2 Cool the system down to -20~10°C under protection, add dropwise 75ml of a THF solution containing 24.8g (0.12mol) of 2-hydroxy-5-(piperazin-1-yl)benzaldehyde and 7g (0.12mol) of glyoxal , and heated to reflux for 2 hours after dropping, followed by TLC until the end of the reaction.

[0035] The reaction solution was filtered to remove solids, after concentration, 500ml of saturated sodium bicarbonate solution was added, stirred with an electric stirrer for half an hour, 400ml of chloroform was added to extract 3 ti...

Embodiment 2

[0036] Example 2: Preparation of 3-[2-hydroxyl-5-(piperazin-1-yl)]phenyl-2-propenal (2)

[0037] N 2 Under air protection, add 80g (1.2mol) of zinc and 4LTHF to a dry four-neck flask with magnetic stirring, start stirring, cool the reaction system to -14~-10°C, and drop in 65mL (0.6mol) of TiCl 4 , Control the temperature of the system at -14~-10°C during the dropping process. After the dropwise addition, the temperature was raised and refluxed for 4.5h, again under N 2 Cool the system to -20~10°C under protection, add dropwise 150ml of a THF solution containing 49.6g (0.24mol) of 2-hydroxy-5-(piperazin-1-yl)benzaldehyde and 14g (0.24mol) of glyoxal , and heated to reflux for 5 hours after dropping, followed by TLC until the end of the reaction.

[0038]The reaction solution was filtered to remove solids, after concentration, 1000ml of saturated sodium bicarbonate solution was added, stirred with an electric stirrer for half an hour, 600ml of chloroform was added to extract...

Embodiment 3

[0039] Example 3: Preparation of 3-[2-hydroxyl-5-(piperazin-1-yl)]phenyl-2-acrylic acid (1)

[0040] Add 40ml of 10% sodium hydroxide solution into a 100ml three-neck flask, drop in 4ml of 5% copper sulfate solution, and stir for 20 minutes with an electric stirrer, the reaction system turns blue. Add 39.4 g (0.17 mol) of 3-[2-hydroxyl-5-(piperazin-1-yl)]phenyl-2-propenal dropwise to the reaction system while stirring. After the drop is complete, heat and reflux for 30 minutes, and the solution It turns yellow, and the solution color is brownish red after cooling, with red precipitate. Filter out the red precipitate, neutralize the filtrate with 1mol / L hydrochloric acid until the pH is 6-7, extract 3 times with 50ml of chloroform respectively, combine the organic phases, decolorize with activated carbon under reflux, filter, dry the filtrate with anhydrous sodium sulfate, and concentrate Chloroform was recovered to obtain 45 g of yellow oil, which contained 88% of 3-[2-hydrox...

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Abstract

The invention discloses a synthesis method of 5-(piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester. The synthesis method comprises the following steps: (1) under the protection of nitrogen, adding zinc powder and tetrahydrofuran to a reactor, dropwise adding TiCl4, adding 2-hydroxyl-5-(piperazin-1-yl) benzaldehyden and glyoxal, and rectifying to obtain 3-[2-hydroxyl-5-(piperazin-1-yl)] phenyl-2-acrylic aldehyde; (2) adding a sodium hydroxide solution and a copper sulfate solution to the reactor, and adding the 3-[2-hydroxyl-5-(piperazin-1-yl)] phenyl-2-acrylic aldehyde while stirring to obtain 3-[2-hydroxyl-5-(piperazin-1-yl)] phenyl-2-acrylic acid; (3) dissolving the 3-[2-hydroxyl-5-(piperazin-1-yl)] phenyl-2-acrylic acid in absolute ethyl alcohol and adding to the reactor, and adding tetrahydrofuran and anhydrous potassium carbonate to obtain the 5-(piperazin-1-yl) benzofuran-2-carboxylic acid ethyl ester. The synthesis route disclosed by the invention is wide in raw material source, simple to operate and outstanding in advantage.

Description

technical field [0001] The invention relates to a method for synthesizing a drug intermediate, in particular to a method for synthesizing an intermediate 5-(piperazin-1-yl)benzofuran-2-carboxylate ethyl ester of vilazodone. Background technique [0002] Vilazodone hydrochloride was approved by the US Food and Drug Administration in January 2011 for the treatment of moderate to severe depression in adults. Clinical trial data show that its curative effect is significantly better than that of placebo, with good tolerance and less adverse reactions. [0003] Ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate is an important intermediate for the preparation of vilazodone hydrochloride. European invention patent (publication number: EP2110374A1) relates to a synthetic method of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate. The synthetic route of the method is as follows: [0004] [0005] In the above route, 2-hydroxy-5-piperazine-benzaldehyde and formaldehyde amine and 2-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/85
CPCC07D307/85
Inventor 宗利郭文娟
Owner BEIJING BEILU PHARM CO LTD
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